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Therapeutic factor xii antibody

A factor and antibody technology, applied in the direction of antibodies, antibody medical components, anticoagulation factor immunoglobulin, etc., can solve problems such as drug administration

Pending Publication Date: 2021-09-21
OREGON HEALTH & SCI UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Consequently, these drugs cannot be administered at their full efficacy doses due to dose-limiting anticoagulant toxicity, and thrombotic vascular occlusion remains the leading cause of death in developed countries

Method used

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  • Therapeutic factor xii antibody
  • Therapeutic factor xii antibody
  • Therapeutic factor xii antibody

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0382] Example 1: Materials and methods

[0383] This example describes the experimental procedures and materials used for the studies described in Example 2.

[0384] Generation of anti-FXII monoclonal antibody (MAb)

[0385] FXII-deficient mice were immunized with recombinant human FXII (Ivanov et al., Blood 2017; 129:1527–1537), and hybridomas were generated by standard methods. Clone 5C12 produced antibodies that bound FXII and FXIIa. Hybridoma cells were subcloned and expanded, and 5C12 was purified using standard procedures, characterized in vitro, and then used for in vivo experiments.

[0386] Characterization of 5C12

[0387] FXII (40 nM) (Haematologic Technologies, Inc., Essex Junction, VT) was incubated with 0-80 nM 5C12 (10 minutes) followed by 1 μg / ml dextran sulfate (20 minutes). Spectrozyme FXIIa (0.5 mM) (Sekisui Diagnostics GmbH, Pfungstadt, Germany) was then added to measure hydrolysis by activated FXII (FXIIa). Next, FXII (100nM) and 5C12 (0-200nM) were...

Embodiment 2

[0398] Example 2: Inhibition of Antibodies to Factor XII in Baboons Reduces Platelet Deposition from Blood in Extracorporeal Membrane Oxygenation

[0399] This example describes the characterization of FXII-specific monoclonal antibody 5C12 and its ability to act as an anticoagulant and reduce platelet aggregation. Furthermore, using a primate model, these studies show that FXII inhibition reduces platelet activation and deposition within membrane oxygenators in both heparinized and non-heparinized baboons.

[0400] 5C12 inhibits FXIIa

[0401] On Western blot, the 5C12 MAb recognized the α and β forms of FXII in humans and baboons and the African green monkey by binding to the protease domain, but not FXII from the other species tested ( Figures 3A-3C ), and prolonged the aPTT of human and baboon plasma mixed with FXII-depleted plasma ( Figure 2A-2B ), but did not extend the other tested species ( Figure 2C-2F ). Increasing the concentration of 5C12 prolongs the clotti...

Embodiment 3

[0416] Example 3: Evaluation of FXIIa inhibition using 5C12 (AB053) in a baboon model of lethal S. aureus exposure

[0417] This Example describes a study evaluating the effect of prophylactic 5C12 (hereinafter "AB053") in a baboon model of fatal systemic inflammatory response syndrome (SIRS). SIRS with or without intravascular coagulation and / or coagulopathy is sometimes observed in patients receiving bactericidal antibiotics to prevent or treat sepsis. Baboons were administered a "saturating" dose of AB053 (10 mg / kg) or no antibody intravenously immediately prior to a continuous 2-hour intravenous infusion of 30 billion heat-inactivated Staphylococcus aureus. Two additional doses of AB053 were administered after 8 hours (10 mg / kg) and 24 hours (5 mg / kg). Vital signs are monitored and blood samples are taken to measure organ function and markers of coagulation, inflammation, and organ damage. Untreated animals (n=3) developed severe SIRS and shock, with significant changes ...

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Abstract

Monoclonal antibodies that bind, such as specifically bind, blood protein factor XII (FXII) are described. The monoclonal antibodies (including antigen-binding fragments thereof) are capable of forming immune complexes with human (FXII) and inhibiting (FXII) activity, resulting in safe anti-inflammatory and anti-thrombotic effects.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of U.S. Provisional Application No. 62 / 772,235, filed November 28, 2018, which is hereby incorporated by reference in its entirety. technical field [0003] The present disclosure relates to potent therapeutic antibodies specific for the blood protein Factor XII (FXII) and their use in methods of medical treatment, including the treatment of thrombosis and hemostatic management. Background technique [0004] Medical devices that come into contact with blood, including catheters, stents, grafts, filters, and extracorporeal organ support systems (ECOS), often result in device-associated thromboembolism, even when medically administered with anticoagulants for thromboprophylaxis, because Existing anticoagulants are not administered at their maximum effective dose due to adverse bleeding side effects (Lavery et al., Adv Drug Deliv Rev 2017; 112:2–11). To maintain patency, perfusion dev...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61P7/02A61K39/00C07K16/36
CPCC07K16/36A61K2039/505C07K2317/24C07K2317/76C07K2317/33C07K2317/92A61K2039/545A61P7/02A61K39/00A61K39/3955A61K45/06A61K49/0002C07K2317/51C07K2317/515C07K2317/56C07K2317/565
Inventor A·格鲁伯E·I·塔克M·瓦利施C·U·洛伦茨
Owner OREGON HEALTH & SCI UNIV
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